Multi-block copolymers comprising a synthetic polymer portion and a poly(amino acid) portion are of great synthetic interest. The poly(amino acid) portion of such polymers is typically prepared by the ring-opening polymerization of an amino acid-N-carboxy-anhydride (NCA). However, methods for preparing the poly(amino acid) block that employ free amines as initiators of the NCA polymerization afford block copolymers with a wide range of polydispersity indices (PDIs) that tend to be quite high. For example, Schlaad reported PDI values of 1.12-1.60 by initiating polymerization with amino-terminated polystyrene. Schlaad (2003 Eur. Chem. J.) also reports a PDI of 7.0 for crude PEG-b-poly(L-benzyl glutamate) copolymers and a PDI of 1.4 after fractionation. Chen (Biomaterials, 2004) reported a PDI of 1.5 for poly(ε-caprolactone) (PCL)-b-poly(ethylene glycol) (PEG)-b-poly (γ-benzyl-L-glutamate)(PBLG). It is believed that these high PDIs are due to the highly reactive nature of the NCAs.
To date, the only reported synthetic methods to prepare multi-block copolymers that contain a poly(amino acid) portion with a narrower distribution of molecular weights, is amine-initiated NCA polymerization utilizing high vacuum techniques developed by Hadjichristidis (Biomacromolecules, 2004), and the nickel-catalyzed coordination-insertion polymerization of NCAs developed by Deming at the University of California-Santa Barbara (see U.S. Pat. No. 6,686,446). Poly(amino acids) synthesized using high vacuum techniques are synthetically challenging to prepare, employ handmade reaction vessels, and require long time periods for reagent purification and complete polymerization to be achieved. Due to these factors, only a few grams of poly(amino acid) can be prepared in a single polymerization reaction. In addition, since multi-block copolymers that comprise a poly(amino acid) portion are typically designed for biological applications, the use of organometallic initiators and catalysts is undesirable.
Accordingly, there remains a need for a method for preparing block copolymers having a synthetic polymer portion and a poly(amino acid) portion wherein the method is well controlled and multiple poly(amino acid) blocks are incorporated.